Wilm's tumor (WT) is an embryonal malignacy of the kidney which affects approximately 1 in 10,000 infants and young children. Matsunaga, Human Genetics, 57: 231-246 (1981). The molecular basis of Wilms' tumor is not well understood.
A subset of Wilms' tumor cases (approximately 2%) occur in association with aniridia (AN2), a defect in the development of the iris, as well as urogenital abnormalities and mental retardation. Miller et al., New Engl. J. Med., 227:922-927 (1964). These disorders form the WAGR syndrome, and can be attributed to constitutional deletions of DNA in band 11p13 on human chromosome 11 in a group of genes known as the WAGR complex. Riccardi et al., Pediatrics, 61:604-610 (1978); Francke, et al., Cytogenet. Cell Genet., 24:185-192 (1979). In these cases, bilateral Wilms' tumors are frequently observed, as are dysplastic changes in surrounding renal tissue (nephroblastomatosis) which are thought to precede malignant transformation. Bove and McAdams, Perspectives on Pediatric Pathol., 3:185-223 (1976). As a recessive oncogene or anti-oncogene, the Wilms' tumor locus curtails the growth of undifferentiated nephretic cells. It conforms generally to a two-mutation model of carcinogenesis and is genetically similar to the retinoblastoma locus on chromosome 13 q. These observations lead to the conclusion that at least in this subset of Wilms' tumors, the inactivation of a gene in 11p13, analogous to the retinoblastoma (RB) gene, is a key event in tumor formation. Considerable effort has been expended in attempting to localize the gene responsible for WT, as is evidenced by the numerous reports describing such efforts. For example, genomic analysis of sporadic Wilms' tumors showing loss of heterozygosity at polymorphic loci supports the localization of Wilms' tumor gene to 11p13. Koufos et al., Nature, 309:170-172 (1984); Orkin et al., Nature, 309:172-174 (1984); Reeve et al., Nature, 309:174-176 (1984); Fearon et al., Nature, 309:176-178 (1984).
Based on additional research, it appears that Wilms' tumor may be caused by loss of function at alternative loci. In studies of two families showing hereditary predisposition to Wilms' tumor, linkage to 11p genetic markers was excluded, indicating the presence of at least one additional Wilms' tumor locus. Grundy et al., Nature, 336:374-376 (1988): Huff et al., Nature, 336:377-378 (1988). Further studies showed loss of heterozygosity in Wilms' tumors at 11p15 rather than 11p13. Reeve et al., Mol. Cell Biol., 9:1799-1803 (1989); Koufos et al., am. J. Hum. Gen., 44:711-719 (1989). Although these data suggest the possibility of additional loci, the 11p13 Wilms' tumor locus is clearly associated with constitutional WAGR deletions and somatic chromosome rearrangements in a subset of sporadic tumors. Lewis et al., Genomics, 3:25-31 (1988).
Despite considerable interest in identifying the Wilms' tumor gene and work focusing on doing so, to the present time, a transcript mapping to the region identified as containing the Wilm's tumor gene has not been identified.